Hypoxia and Inflammation

Series edited by M. Celeste Simon

Inflammation is a primary response to injury and or infection, allowing the body to eliminate pathogens and/or damaged tissue and to initiate repair processes. Low oxygen levels, or hypoxia, is a key feature of inflamed tissue and is due to damage to the local vasculature and increased oxygen consumption by pathogens and infiltrating immune cells. In addition to being a feature of inflammation, hypoxia also induces and regulates the inflammatory response by inducing the release of inflammatory cytokines, directing immune cell infiltration, and tuning the responses of the immune cells themselves. These effects are largely mediated by a family of hypoxia-inducible transcription factors (HIFs), which serve as the master regulators of cellular responses to inadequate oxygenation and HIFs and their regulatory factors are now emerging as therapeutic targets in a number of disease states. Reviews in this series discuss the roles of hypoxia and HIFs in the regulation of inflammatory pathways, immune cell metabolism, mucosal inflammation, the tumor microenvironment, intestinal inflammation and colorectal cancer, and recovery from radiation-induced gastrointestinal toxicity. Together, these reviews identify a number of hypoxia-regulated processes that could potentially be targeted to modulate inflammation.

Abstract

Hypoxia is a prominent characteristic of many acute or chronic inflammatory diseases, and exerts significant influence on their progression. Macrophages and neutrophils are major cellular components of innate immunity and contribute not only to O2 deprivation at the site of inflammation, but also alter many of their functions in response to hypoxia to either facilitate or suppress inflammation. Hypoxia stabilizes HIF-αs in macrophages and neutrophils, and these O2-sensitive transcription factors are key regulators of inflammatory responses in myeloid cells. In this review, we will summarize our current understanding of the role of HIF-αs in shaping macrophage and neutrophil functions in the pathogenesis and progression of multiple inflammatory diseases.

Abstract

The role of tumor-associated macrophages (TAMs) in cancer is often correlated with poor prognosis, even though this statement should be interpreted with care, as the effects of macrophages primarily depend on their localization within the tumor. This versatile cell type orchestrates a broad spectrum of biological functions and exerts very complex and even opposing functions on cell death, immune stimulation or suppression, and angiogenesis, resulting in an overall pro- or antitumoral effect. We are only beginning to understand the environmental cues that contribute to transient retention of macrophages in a specific phenotype. It has become clear that hypoxia shapes and induces specific macrophage phenotypes that serve tumor malignancy, as hypoxia promotes immune evasion, angiogenesis, tumor cell survival, and metastatic dissemination. Additionally, TAMs in the hypoxic niches within the tumor are known to mediate resistance to several anticancer treatments and to promote cancer relapse. Thus, a careful characterization and understanding of this macrophage differentiation state is needed in order to efficiently tailor cancer therapy.

Abstract

Mucosal surfaces are lined by epithelial cells and provide an important barrier to the flux of antigens from the outside. This barrier is provided at a number of levels, including epithelial junctional complexes, mucus production, and mucosa-derived antimicrobials. Tissue metabolism is central to the maintenance of homeostasis in the mucosa. In the intestine, for example, baseline pO2 levels are uniquely low due to counter-current blood flow and the presence of large numbers of bacteria. As such, hypoxia and HIF signaling predominates normal intestinal metabolism and barrier regulation during both homeostasis and active inflammation. Contributing factors that elicit important adaptive responses within the mucosa include the transcriptional regulation of tight junction proteins, metabolic regulation of barrier components, and changes in autophagic flux. Here, we review recent literature around the topic of hypoxia and barrier function in health and during disease.

Abstract

The tumor immune response is in a dynamic balance between antitumor mechanisms, which serve to decrease cancer growth, and the protumor inflammatory response, which increases immune tolerance, cell survival, and proliferation. Hypoxia and expression of HIF-1α and HIF-2α are characteristic features of all solid tumors. HIF signaling serves as a major adaptive mechanism in tumor growth in a hypoxic microenvironment. HIFs represent a critical signaling node in the switch to protumorigenic inflammatory responses through recruitment of protumor immune cells and altered immune cell effector functions to suppress antitumor immune responses and promote tumor growth through direct growth-promoting cytokine production, angiogenesis, and ROS production. Modulating HIF function will be an important mechanism to dampen the tumor-promoting inflammatory response and inhibit cancer growth.

Abstract

HIF1α is a common component of pathways involved in the control of cellular metabolism and has a role in regulating immune cell effector functions. Additionally, HIF1α is critical for the maturation of dendritic cells and for the activation of T cells. HIF1α is induced in LPS-activated macrophages, where it is critically involved in glycolysis and the induction of proinflammatory genes, notably Il1b. The mechanism of LPS-stimulated HIF1α induction involves succinate, which inhibits prolyl hydroxylases (PHDs). Pyruvate kinase M2 (PKM2) is also induced and interacts with and promotes the function of HIF1α. In another critical inflammatory cell type, Th17 cells, HIF1α acts via the retinoic acid–related orphan receptor-γt (RORγt) to drive Th17 differentiation. HIF1α is therefore a key reprogrammer of metabolism in inflammatory cells that promotes inflammatory gene expression.

Abstract

Radiotherapy is an effective treatment strategy for cancer, but a significant proportion of patients experience radiation-induced toxicity due to damage to normal tissue in the irradiation field. The use of chemical or biological approaches aimed at reducing or preventing normal tissue toxicity induced by radiotherapy is a long-held goal. Hypoxia-inducible factors (HIFs) regulate the production of factors that may protect several cellular compartments affected by radiation-induced toxicity. Pharmacological inhibitors of prolyl hydroxylase domain–containing enzymes (PHDs), which result in stabilization of HIFs, have recently been proposed as a new class of radioprotectors. In this review, radiation-induced toxicity in the gastrointestinal (GI) tract and the main cellular compartments studied in this context will be discussed. The effects of PHD inhibition on GI radioprotection will be described in detail.

Abstract

Uncontrolled inflammation underpins a diverse range of diseases where effective therapy remains an unmet clinical need. Hypoxia is a prominent feature of the inflammatory microenvironment that regulates key transcription factors including HIF and NF-κB in both innate and adaptive immune cells. In turn, altered activity of the pathways controlled by these factors can affect the course of inflammation through the regulation of immune cell development and function. In this review, we will discuss these pathways and the oxygen sensors that confer hypoxic sensitivity in immune cells. Furthermore, we will describe how hypoxia-dependent pathways contribute to immunity and discuss their potential as therapeutic targets in inflammatory and infectious disease.